The compound of formula I (herein sometimes designated as compound (I) or 5) is a non-peptidic, highly selective small-molecule antagonist of the protein-protein interaction between MDM2 and tumor suppressor protein p53. Inhibition of MDM2, the principal cellular antagonist of p53, leads to p53 pathway activation and apoptosis of cells carrying potential oncogenic mutations. This therapeutic approach (MDM2 inhibition) is currently under development as a novel strategy for cancer treatment. A previous synthesis of Compound I was reported in U.S. patent application Ser. No. 12/702,402, where Compound IIa is obtained from the racemate II by a chiral column chromatography method and coupled with Compound III followed by hydrolysis of the ester to give Compound I as shown in Scheme 1. The overall yield of compound (I) JB, 17/Jan./2014 relative to starting material of compound (IV) as used herein (see e.g. scheme 5) using this process is about 10%. There remains a need to develop improved methods for large, industrial scale production of compound (I).
